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240
Journal of Pain and Symptom Management
Vol. 16 No. 4 October 1998
Original Article
Managing Morphine-Induced Constipation:
A Controlled Comparison of an Ayurvedic
Formulation and Senna
P. R. Ramesh, K. Suresh Kumar, M. R. Rajagopal, P. Balachandran and P. K. Warrier
Pain and Palliative Care Clinic (K.S.K., M.R.R.), Calicut Medical College, Calicut, India, and Arya
Vaidya Sala (P.R.R.., P.B., P.K.W.), Kottakkal, Kerala, India
Abstract
Constipation is a frequent cause of distress in advanced cancer. A palliative care unit in
Kerala, a southern state of India, conducted a controlled trial comparing a liquid Ayurvedic
(herbal) preparation (Misrakasneham) with a conventional laxative tablet (Sofsena) in the
management of opioid-induced constipation in patients with advanced cancer. Although there
was no statistically significant difference in the apparent degree of laxative action between the
two, the results indicate that the small volume of the drug required for effective laxative action,
the tolerable taste, the once-daily dose, the acceptable side effect profile, and the low cost make
Misrakasneham a good choice for prophylaxis in opioid-induced constipation. There is a
need for further studies of Ayurvedic medicines in palliative care. J Pain Symptom Manage
1998;16:240–244. © U.S. Cancer Pain Relief Committee, 1998.
Key Words
Cancer care, constipation, morphine, alternative medicine, Ayurveda
Introduction
Constipation is a frequent cause of distress
in advanced cancer.1 It is generally multifactorial in origin and may be caused by poor diet,
decreased activity, local disease, and drugs—
notably opioids.2 In the Pain and Palliative
Care Clinic at the Calicut Medical College,
30% of patients have head and neck cancer
and associated dysphagia. Most of the patients
are very poor and are not able to buy drugs
regularly. For such patients, a cheap, small-volume liquid laxative would be preferable. However, liquid laxatives like lactulose and cremaffin (milk of magnesia 11.25 ml, liq. paraffin
Address reprint requests to: Dr. P. R. Ramesh, Arya Vaidya Sala, Kottakkal (P. O.), Malappuram Dist., 676
503, Kerala, India.
Accepted for publication: February 4, 1998.
© U.S. Cancer Pain Relief Committee, 1998
Published by Elsevier, New York, New York
3.75 ml per 15 ml emulsion) are both costly
(Rs. 51 per 100 ml and Rs. 23 per 200 ml respectively*) and are required in relatively large
volumes.3 Many patients find them unpalatable. As a part of an ongoing effort to select a
more ideal preparation, an attempt has been
made to study the efficacy of an Ayurvedic
preparation. Ayurveda is the most popular indigenous Indian system of medicine, in which
materials mainly of plant or animal origin are
used for preparing decoctions, powders, medicated oils, pills, or other medicines.
Misrakasneham is a centuries-old Ayurvedic
liquid purgative containing 21 kinds of herbs,
castor oil, ghee, and milk. A clinical trial was
undertaken with this preparation to determine
its effect on opioid-induced constipation. The
*$1 ⫽ approximately Rs. 42.
0885-3924/98/$19.00
PII S0885-3924(98)00080-3
Vol. 16 No. 4 October 1998
Managing Morphine-Induced Constipation
Table 1
Exclusion Criteria
Infants and children
Patients with intestinal obstruction
Patients already on laxatives
Patients who are constipated even before the intake
of morphine
Patients already undergoing Ayurvedic therapy as some
medicines may have a laxative action
Patients who refuse informed consent
aim was to compare the efficacy of Misrakesneham with that of a conventional laxative, Sofsena
tablet, in the management of opioid-induced
constipation in patients with advanced cancer.
Methods
The study was conducted on patients with
advanced cancer aged 15 years and older who
were started on oral morphine for the first
time and who gave informed consent. The exclusion criteria are given in Table 1.
Fifty patients were randomly allocated to the
two study groups (25 each) by drawing lots
(sampling with replacement). The difference
between the physical forms of the two drugs
necessitated an open trial rather than a double-blind study, as has been done in similar
other studies.4 Laxatives were given as a pro-
241
phylactic measure to the patients who were
started on oral morphine for the first time.
One group received Misrakasneham (Table 2);
the other group received Sofsena tablets (purified senna extract 60 mg containing 12 mg
senna glucocides as calcium salts). The diagnoses, demographics and drugs administered
to the study patients are described in Tables 3a
and 3b.
The study period was 14 days. The laxatives
were administered in three steps (Table 4).
Step 1 was given first and then followed respectively by step 2 and step 3 if the previous step
failed. An interval of 2 days was allowed between steps. The patients were examined every
3 days during the first week and on the last day
of the second week. Each day’s bowel movements were recorded in a specific format in accordance with the criteria given in Table 5.
These criteria were set on the basis of subjective feeling of satisfaction, in view of the fact
that the expectation and achievement of bowel
movement are widely varying parameters.5
Results
Eighty percent (N ⫽ 20) of the patients in
the Misrakasneham group and 64% (N ⫽ 16) of
the patients in the Sofsena group completed the
study. Of those who completed the study, 85%
Table 2
Ingredients of Misrakasnehama
Sanskrit name
Pippali
Amalaki
Draksha
Syama
Danthi
Dravanthi
Kramuka
Kutarani
Samkhani
Charmasahva
Svarnaksheeri
Gavakshi
Sikhari
Rajani
Chinnaroha
Karanja
Basthantri
Vyathighatha
Sigru
Bahurasa
Thikshnavrikshaphala
Botanical name
Wt. (mg)
Piper longum Linn.
Phyllanthus emblica Linn.
Vitis vinifera Linn.
Operculina turpethum (Linn.) Silva Manso (white)
Baliospermum montanum (Willd.) Muell.- Arg. (purified)
Jatropha curcas Linn.
Areca catechu Linn.
Operculina turpethum (Linn.) Silva Manso (black)
Clitoria ternatea Linn.
Acacia sinuata (Lour.) Merr.
Argemone mexicana Linn.
Cucumis trigonus Roxb.
Achyranthes aspera Linn.
Curcuma longa Linn.
Tinospora cordifolia (Willd.) Miers ex Hook.f.& Thoms.
Pongamia glabra Vent.
Argyreia speciosa Sweet
Casia fistula Linn.
Moringa oleifera Lam.
Saccharum officinarum Linn.
Croton tiglium Linn. (purified)
780
780
780
780
708
780
780
780
780
780
780
780
780
780
780
780
780
780
780
780
780
a100 ml of the medicine is prepared by the evaporative processing of the following items in accordance with Ref. 8:
milk 600 ml; castor oil 50 ml; ghee 50 ml.
242
Ramesh et al.
Table 3a
Diagnosis and Demographics of Study
Patients (N ⴝ 50)
Number of patients
Misrakasneham
group
Sofsena
group
9
3
3
1
3
1
2
1
0
1
0
1
7
3
3
2
2
0
1
0
1
3
2
0
Diagnosis
Carcinoma of lung
Carcinoma of tongue
Carcinoma of breast
Carcinoma of esophagus
Carcinoma of oropharynx
Carcinoma of tonsil
Hepatocellular carcinoma
Mulitple myeloma
Carcinoma of ovary
Carcinoma of cervix
Carcinoma of cheek
Carcinoma of penis
Acute myelogenous
leukemia
Age distribution
⬍ 30
31–40
41–50
51–60
61–70
Sex distribution
Male
Female
0
1
25
25
1
4
4
11
5
1
2
6
10
6
25
25
17
8
15
10
25
25
(N ⫽ 17) of the Misrakasneham group and 69%
(N ⫽ 11) of the Sofsena group had satisfactory
bowel movements, and 15% (N ⫽ 3) and 31%
(N ⫽ 5) of the respective groups did not have
Vol. 16 No. 4 October 1998
satisfactory bowel movements. These figures
suggest a trend in favor of Misrakasneham from
the point of view of efficacy, even though the
difference is not statistically significant (P ⬎
0.2; chi-square test). Among those with satisfactory bowel movements, 47% (N ⫽ 8) from the
Misrakasneham group and 45% (N ⫽ 5) from the
Sofsena group had satisfactory bowel movements with step 1. Twenty-nine percent (N ⫽
5) from the Misrakasneham group and 55% (N ⫽
6) from the Sofsena group had satisfactory
bowel movement with step 2, and 24% (N ⫽ 4)
from the Misrakasneham group and none from
the Sofsena group had satisfactory bowel movement with step 3 (Table 6). Details of those
cases with unsatisfactory bowel movements are
given in Table 7.
Among those who did not complete the
study, one from the Misrakasneham group and
four from the Sofsena group dropped out due
to irregular laxative administration. Two from
the Misrakasneham group died during the
course of the study. Two each from both the
groups were lost to follow-up. Morphine was
withdrawn from two patients in the Sofsena
group and these patients were dropped from
the study. One from the Sofsena group dropped
out as he was getting good bowel movement
without laxative (Table 8).
Discussion
Ayurveda literally means the science of life
and the positive and negative aspects of life are
Table 3b
Drugs Taken by Study Patients
Number of patients
Morphine dose/24 hr
15 mg
30 mg
45 mg
60 mg
Other medications
Paracetamol
Diclofenac sodium
Metoclopramide
Amitriptyline
Ranitidine
Haloperidol
Prednisolone
Dicyclomine
Dose/24 hr
2–5 g
150 mg
10–30 mg
12.5–25 mg
300 mg
2.5 mg
10–20 mg
20 mg
Misrakasneham
group
Sofsena
group
8
12
0
5
9
10
2
4
25
25
9
12
20
4
5
4
1
0
10
11
19
3
4
4
1
1
Vol. 16 No. 4 October 1998
Managing Morphine-Induced Constipation
243
Table 4
Administration of Misrakasneham and Sofsena
Laxative
Misrakasnehama
Sofsena tablets
aUsually
Step 1
Step 2
Step 3
2.5 ml
2 tabs at night
5 ml
4 tabs at night
10 ml
2 tabs in the morning ⫹ 4 tabs at night
mixed with 30 ml of warm milk or warm water; given in the morning.
explained in a unique way in this science. The
literature on the principles and practices of
Ayurveda are written in the classical Hindu language of Sanskrit and are dated to 400 B.C.6
Ayurveda has, essentially, two components;
(i) the Svasthavritha (healthy man’s regimen),
which deals with the orderly upkeep of health
and (ii) Athuravritha (patient’s regimen),
which is all about the eradication of diseases.
Ayurveda perceives man as an integral part of
nature and its approach to well-being is philosophical in principle and holistic in technique.
Every ailment is conceived as a psychosomatic
manifestation and its eradication is functional
and integrative, rather than symptomatic or
factorial. Every human being is seen to occupy,
constitutionally, a unique state of three basic
bodily humors (Vata, Pitta, and Kapha). Any
upset occurring to this nascent state of balance
is manifested as an ailment and the therapy is
directed to regain the original state. This is the
reason that it is commonly stated that the
Ayurvedic treatment is for the patient and not
for the ailment. Thus, the therapy may vary for
different patients displaying the same symptoms. This principle was compromised in the
use of the same Ayurvedic laxative for all paTable 5
Assessment of Laxative Efficacy
Observationa
No bowel movement
Unsatisfactory bowel
movement:
a. with side effects (nausea,
vomiting, and colic)
b. without side effects
Satisfactory bowel movement
with side effects
Satisfactory bowel movement
with no side effects
Efficacy
Grade
Failure
0
Poor
1
Moderate
2
Good
3
aDefinitions:
1. Satisfactory bowel movement: As it is a subjective perception of each
individual it was defined as the comfortable feeling that a patient
experienced after getting a free, effortless bowel movement at a frequency acceptable to him.
2. Unsatisfactory bowel movement: It was defined as the uncomfortable
feelings that the patient experienced as the bowel movements were
not up to his level of expectations either in frequency or ease.
tients on oral morphine because a scientific
evaluation of the drug using modern methodology mandated such a compromise.
Misrakasneham is a centuries-old combination
used in Ayurveda as a purgative in constipated
patients. The mode of processing, the ingredients and the indications for this formulation
are described in a classic Ayurvedic literature
called Ashtangahridayam7 which is about 1300
years old and is in the official Formulary.8 The
individual ingredients are described with botanical and Ayurvedic details in a recent publication.9 Although used as a “purgative” in
Ayurveda, the present study evaluated small
doses of Misrakasneham as a laxative. Sofsena, a
freely available stimulant laxative commonly used
in India, was employed as the comparator.
Patients who had regular bowel movements
with Misrakasneham were also satisfied with its
easy administration. As it is a liquid preparation that can be used in a small dose (2.5 to 10
ml), it was well accepted by the patients who
were benefitted by it, especially those with dysphagia from head and neck lesions. The latency of action of Sofsena is 6–12 hours,10 compared to an observed latency period of 4–6
hours in the case of Misrakasneham. The cost of
2.5 ml Misrakasneham is less than Rs. 1, compared to Rs. 1.60 for an equivalent dose of Sofsena tablet. The patients did not complain
about the taste of the laxative.
Misrakasneham appears to be acting as a stimulant laxative. The pharmacokinetics and pharmacodynamics of its components are not clearly
understood. It is assumed that the combination of the 21 herbs together with castor oil,
milk, and ghee produces the effective laxative
Table 6
Details of Cases with Satisfactory Bowel Movements
Step
1
2
3
Misrakasneham
No. of cases
Sofsena
No. of cases
8 (47%)
5 (29%)
4 (24%)
5 (45%)
6 (55%)
0 (0%)
244
Ramesh et al.
Table 8
Details of Drop-outs from the Study
Table 7
Details of Cases with Unsatisfactory
Bowel Movements
Number of cases
Number of cases
a) Vomited in step 1
and colica
b) No bowel movement
even with step 3b
Total
Vol. 16 No. 4 October 1998
Reason
Misrakasneham
Sofsena
2
0
1
3
5
5
aSee
text for description.
bAll six cases were managed with repeated use of bisacodyl suppository and glycerine enema.
action in this small dose. In comparison, castor
oil, on its own, is unpalatable and not as effective, as it needs higher adult dosage.11 It was interesting to note that 4 of the 17 patients
(24%) who exhibited satisfactory results in the
Misrakasneham group took it only once in two
or three days. Anecdotedly, higher doses (10–
20 ml) of the Misrakasneham have achieved results in patients who have not responded to
conventional laxatives at all.
Two patients in the Misrakasneham group
stopped the laxative after the first dose, complaining of nausea, vomiting, and colicky pain.
They did not have bowel movement with that
dose. One of these patients had carcinoma of
the tonsil and responded well to bisacodyl 5–10
mg at night, whereas the other patient who
had hepatocellular carcinoma, continued vomiting even after stopping Misrakasneham, despite antiemetics. She stopped vomiting after
discontinuing the low dose of morphine (2.5
mg q4h) that she was taking.
It is tentatively concluded from this study
that Misrakasneham has the potential to be used
as an alternate therapeutic tool for managing
morphine-induced constipation as a part of
palliative care of patients with advanced cancer. Viewed from the perspective of palatability, cost effectiveness, and low side effect profile, the formulation appears to be a good choice.
Further rigorous studies are needed to establish the preliminary results presented here.
Acknowledgment
The authors express their sincere gratitude
to Dr. Robert Twycross for the very useful dis-
Irregular laxative
administration
Death
No follow-up
Morphine-withdrawn
Good bowel movement
without laxative
Total
Misrakasneham
Sofsena
1 (20%)
2 (40%)
2 (40%)
0 (0%)
4 (45%)
0 (0%)
2 (22%)
2 (22%)
0 (0%)
5 (100%)
1 (11%)
9 (100%)
cussions and guidance during the study and
while preparing the manuscript. They also
thank the patients, volunteers, and staff of the
Pain and Palliative Care Clinic for their excellent support to the study. Thanks are also due
to Dr. T.S. Murali and Dr. C. Ramankutty for
suggestions and to Mrs. Saraswathy, Mrs. Preetha Ramesh, and Mr. P.M. Vasudevan for secretarial support.
References
1. Twycross RG, Lack, SA. Control of alimentary
symptoms in far advanced cancer. Edinburgh:
Churchill Livingstone, 1986.
2. Sykes N. Prog Palliative Care 1996;4:170.
3. Sykes NP. A volunteer model for the comparison of laxatives in opioid-related constipation. J Pain
Symptom Manage 1996;11:363.
4. Sykes NP. A clinical comparison of laxative in a
hospice. Palliative Med 1991;5:307.
5. Connell AM, Hilton C, Irvine G, Lennard-Jones
JE, Misicwicz JJ. Variation in bowel habit in two population samples. Br Med J 1965;11:1095.
6. Bhishagratna KL. Susrutha samhita, Vol. I (English translation). Choukhamba Sanskrit series.
Varanasi, 1991.
7. Kunte AM, Shasthri NKR. Ashtangahridyam of
Vagbhata. Choukamba Orientalia. Varanasi, 1982.
8. The Ayurvedic Formulary of India, Part I. Govt.
of India, Ministry of Health and Family Planning,
Department of Health, 1978, 79.
9. Warrier PK, Nambiar VPK, Ramankutty C. Indian medicinal plants—a compendium of 500 species, in 5 volumes. Chennai: Orient Longman Ltd.,
1993–1996.
10. British National Formulary, 1989, No. 18:67.
11. British National Formulary, 1989, No. 18:66.